Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P05231 (interleukin-6)
 23,907 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Signal transducer and activator of transcription 3 (STAT3) mediates signals of various growth factors and cytokines, including interleukin-6 (IL-6). In certain IL-6-responsive cell lines, the stat3 gene is autoregulated by STAT3 through a composite IL-6 response element in its promoter that contains a STAT3-binding element (SBE) and a cyclic AMP-responsive element. To reveal the nature and roles of the stat3 autoregulation in vivo, we generated mice that harbor a mutation in the SBE (stat3(mSBE)). The intact SBE was crucial for IL-6-induced stat3 gene activation in the spleen, especially in the red pulp region, the kidney, and both mature and immature T lymphocytes. The SBE was not required, however, for IL-6-induced stat3 gene activation in hepatocytes. T lymphocytes from the stat3(mSBE/mSBE) mice were more susceptible to apoptosis despite the presence of IL-6 than those from wild-type mice. Consistent with this, IL-6-dependent activation of the Pim-1 and junB genes, direct target genes for STAT3, was attenuated in T lymphocytes of the stat3(mSBE/mSBE) mice. Thus, the tissue-specific autoregulation of the stat3 gene operates in vivo and plays a role in IL-6-induced antiapoptotic signaling in T cells.
 ...
PMID:Tissue-specific autoregulation of the stat3 gene and its role in interleukin-6-induced survival signals in T cells. 1153 49

We reported previously an important role of cyclic AMP-response element (CRE) for the induction of interleukin-6 gene expression by angiotensin II (AngII). We examined signaling pathways that are responsible for AngII-induced phosphorylation of CRE-binding protein (CREB) at serine 133 that is a critical marker for the activation in rat vascular smooth muscle cells (VSMC). AngII time dependently induced phosphorylation of CREB with a peak at 5 min. The AngII-induced phosphorylation of CREB was blocked by CV11974, an AngII type I receptor antagonist, suggesting that AngII type I receptor may mediate the phosphorylation of CREB. Inhibition of extracellular signal-regulated protein kinase (ERK) by PD98059 or inhibition of p38 mitogen-activated protein kinase (MAPK) by SB203580 partially inhibited AngII-induced CREB phosphorylation. A protein kinase A inhibitor, H89, also partially suppressed AngII-induced CREB phosphorylation. Inhibition of epidermal growth factor-receptor by AG1478 suppressed the AngII-induced CREB phosphorylation as well as activation of ERK and p38MAPK. Overexpression of the dominant negative form of CREB by an adenovirus vector suppressed AngII-induced c-fos expression and incorporation of [(3)H]leucine to VSMC. These findings suggest that AngII may activate multiple signaling pathways involving two MAPK pathways and protein kinase A, all of which contribute to the activation of CREB. Transactivation of epidermal growth factor-receptor is also critical for AngII-induced CREB phosphorylation. Activation of CREB may be important for the regulation of gene expression and hypertrophy of VSMC induced by AngII.
 ...
PMID:Critical role of cAMP-response element-binding protein for angiotensin II-induced hypertrophy of vascular smooth muscle cells. 1190 26

1. We examined the effects of endogenous prostaglandin E(2) (PGE(2)) on the production of interleukin-6 (IL-6), macrophage colony stimulating factor (M-CSF), and vascular endothelial growth factor (VEGF) by interleukin-1beta (IL-1beta)-stimulated human synovial fibroblasts. 2. NS-398 (1 microM), a cyclo-oxygenase-2 (COX-2) inhibitor, inhibited IL-6 and VEGF production (35+/-4% and 26+/-2%, respectively) but enhanced M-CSF production (38+/-4%) by IL-1beta (1 ng ml(-1)) in synovial fibroblasts isolated from patients with osteoarthritis (OA) and rheumatoid arthritis (RA). Exogenous PGE(2) completely abolished the effects of NS-398 on the production of each mediator by OA fibroblasts stimulated with IL-1beta. 3. 8-Bromo cyclic AMP and dibutyryl cyclic AMP, cyclic AMP analogues, mimicked the effects of PGE(2) on IL-6, M-CSF, and VEGF production by OA fibroblasts. 4. The EP(2) selective receptor agonist ONO-AE1-259 (2 nM) and the EP(4) selective receptor agonist ONO-AE1-329 (2 or 20 nM), but not the EP(1) selective receptor agonist ONO-DI-004 (1 microM) and the EP(3) selective receptor agonist ONO-AE-248 (1 microM), replaced the effects of PGE(2) on IL-6, M-CSF, and VEGF production by OA and RA fibroblasts stimulated with IL-1beta in the presence of NS-398. 5. Both OA and RA fibroblasts expressed mRNA encoding EP(2) and EP(4) but not EP(1) receptors. In addition, up-regulation of EP(2) and EP(4) receptor mRNAs was observed at 3 h after IL-1beta treatment. 6. These results suggest that endogenous PGE(2) regulates the production of IL-6, M-CSF, and VEGF by IL-1beta-stimulated human synovial fibroblasts through the activation of EP(2) and EP(4) receptors with increase in cyclic AMP.
 ...
PMID:Regulation by PGE2 of the production of interleukin-6, macrophage colony stimulating factor, and vascular endothelial growth factor in human synovial fibroblasts. 1201 Jul 78

We have previously shown that adenosine is formed in the intestinal lumen during active inflammation from neutrophil-derived 5'-AMP. Acting through the adenosine A2b receptor (A2bR), the luminally derived adenosine induces vectorial chloride secretion and a polarized secretion of interleukin-6 to the intestinal lumen. Although some G protein-coupled receptors interact with anchoring or signaling molecules, not much is known in this critical area for the A2bR. We used the model intestinal epithelial cell line, T84, and Caco2-BBE cells stably transfected with GFP-A2b receptor to study the intestinal A2bR. The A2bR is present in both the apical and basolateral membranes of intestinal epithelia. Apical or basolateral stimulation of the A2bR induces recruitment of the receptor to the plasma membrane and caveolar fractions. The A2bR co-immunoprecipitates with E3KARP and ezrin upon agonist stimulation. Ezrin interacts with E3KARP and PKA and the interaction between ezrin and E3KARP is enhanced by agonist stimulation. Our data suggest that the A2bR is recruited to the plasma membrane upon apical or basolateral agonist stimulation and interacts with E3KARP and ezrin. We speculate that such an interaction may not only anchor the A2bR to the plasma membrane but may also function to stabilize the receptor in a signaling complex in the plasma membrane.
 ...
PMID:The adenosine 2b receptor is recruited to the plasma membrane and associates with E3KARP and Ezrin upon agonist stimulation. 1208 47

The chemokine stromal cell-derived factor-1 (SDF-1) and its receptor CXCR4 control the migration of neurons and microglial cells in the central nervous system. Although functional CXCR4 is also expressed by astroglia, recent studies have failed to observe a chemotactic response of these cells to SDF-1. Here, we demonstrate that SDF-1-dependent chemotaxis can be induced by treating cultured cortical astroglia with either dibutyryl cyclic AMP (dbcAMP; 10(-4) m) or interleukin-6 (IL-6; 10 ng/ml). Flow cytometric analysis revealed that both the dbcAMP- and IL-6-induced onset of SDF-1-dependent chemotaxis of astroglia are due to the increased cell surface expression of CXCR4. In addition, dbcAMP and IL-6 also increased CXCR4 transcript levels, further suggesting that both treatments primarily affect CXCR4 surface expression in astroglia by stimulation of gene expression. Moreover, unlike the case with IL-6 and dbcAMP, which allowed for an optimal chemotactic response to SDF-1 only after 48 h, a similar chemotactic response, associated with an increase in CXCR4 cell surface expression, already occurred after 24 h when astroglial cultures were maintained with medium conditioned by IL-6- or dbcAMP-pretreated astrocytes, indicating that the stimulatory effects of IL-6 and cAMP on CXCR4 cell surface expression involve a secondary mechanism. The findings that elevated extracellular levels of IL-6 or factors positively coupled to cAMP result in increased CXCR4 cell surface expression levels and subsequent SDF-1-dependent chemotaxis in central nervous system astrocytes point to a crucial role of this chemokine during reactive gliosis and human immunodeficiency virus-mediated dementia.
 ...
PMID:Interleukin-6 and cAMP induce stromal cell-derived factor-1 chemotaxis in astroglia by up-regulating CXCR4 cell surface expression. Implications for brain inflammation. 1217 12

Pituicytes, the glial cells of the neurohypophysis, secrete interleukin-6 upon stimulation with various inflammatory mediators, i.e. lipopolysaccharide. Previous studies have identified several receptors on pituicytes. This study investigates the effect of GABA(B) receptor activation on interleukin-6 release from pituicytes. Cultured murine pituicytes were stimulated for 24 h with lipopolysaccharide (0.5 ng/ml) to give a significant interleukin-6 release compared to control. The interleukin-6 release was significantly potentiated by the GABA(B) receptor agonist (R)-4-amino-3-(4-chlorophenyl) butanoic acid (R-baclofen; 10, 100 or 500 microM). However, R-baclofen itself (10, 100 or 500 microM) did not stimulate the interleukin-6 secretion. Furthermore, the potent GABA(B) receptor antagonists 3-[[(3,4-Dichlorophenyl)methyl]amino]propyl]diethoxymethyl) phosphinic acid (CGP52432; 30 or 300 microM) and (RS)-3-Amino-2-(4-chlorophenyl)-2-hydroxypropyl-sulphonic acid (2-OH-saclofen; 10 or 100 microM) did not remove the effect of R-baclofen (100 microM). Gamma-amino butyric acid (GABA; 30 or 300 microM) did not alter the lipopolysaccharide-mediated interleukin-6 response. After 30 min, intracellular cyclic AMP (cAMP) was higher in cells stimulated with lipopolysaccharide compared to control, and R-baclofen significantly inhibited this increase in cAMP. Nevertheless, neither lipopolysaccharide nor R-baclofen had any effect on intracellular cAMP after 24 h of stimulation. The results suggest that the effect of R-baclofen on lipopolysaccharide-stimulated interleukin-6 secretion is independent of GABA(B) receptors.
 ...
PMID:Baclofen influences lipopolysaccharide-mediated interleukin-6 release from murine pituicytes. 1223 93

Inhalation of organic dust from a swine-confinement building leads to an intense inflammatory reaction with an increased number of inflammatory cells and mediators in the upper and lower respiratory tract of previously unexposed subjects. In vitro the dust induces cytokine release from epithelial cells and alveolar macrophages. It is known that intracellular cyclic AMP (cAMP) contributes to the regulation of inflammatory responses. We therefore investigated whether 8-Bromo-cAMP, a cell membrane-permeable cAMP analogue, would influence release of the cytokines interleukin-6 (IL-6) and IL-8 in a human airway epithelial cell line, A549, exposed to a suspension of the organic dust, and to a supernatant prepared by centrifugation (at low g-force) of a suspension of dust. The large particulate matter was thus sedimented, leaving bacteria, whole and cell wall constituents in the supernatant. Cytokine release was measured with enzyme-linked immunosorbent assay (ELISA). The cytokine release induced by a supernatant was 23% (IL-6) and 27% (IL-8) of the release induced by a dust suspension. 8-Bromo-cAMP (1 mM) doubled basal IL-6 release and IL-6 release induced by a dust supernatant (P<0.01), and increased IL-6 release induced by a dust suspension by 19% (P<0.05). 8-Bromo-cAMP did not affect basal IL-8 release, partially inhibited (28%) the release of IL-8 induced by a dust suspension (P<0.01), but increased IL-8 release induced by a dust supernatant by 13% (P<0.05). In summary, expression of the cytokines IL-6 and IL-8 is differentially regulated by 8-Bromo-cAMP, both with regard to basal and dust-induced release. The results indicate that 8-Bromo-cAMP attenuated IL-8 release by affecting signaling transductions induced by the particulate fraction.
 ...
PMID:Effects by 8-bromo-cyclicAMP on basal and organic dust-induced release of interleukin-6 and interleukin-8 in A549 human airway epithelial cells. 1255 10

The involvement of P2Y receptors, which are activated by extracellular nucleotides, in proliferative regulation of human lung epithelial cells is unclear. Here we show that extracellular ATP and UTP stimulate bromodeoxyuridine (BrdU) incorporation into epithelial cell lines. The nucleotide efficacy profile [ATP = ADP > UDP >or= UTP > adenosine >or= 2-methylthioadenosine-5'-diphosphate, with alpha,beta-methylene adenosine 5'-triphosphate, 2',3'-O-(4-benzoylbenzoyl)adenosine 5'-triphosphate, AMP, UMP, and ATPalphaS inactive] and PCR analysis indicate involvement of P2Y2 and P2Y6 receptors. The signal transduction pathway, which, via the P2Y2 receptor, transmits the proliferative activity of ATP or UTP in A549 cells downstream of phospholipase C, depends on Ca2+/calmodulin-dependent protein kinase II and nuclear factor-kappaB, but not on protein kinase C. Signaling does not involve the mitogen-activated protein kinases extracellular signal-regulated kinases-1 and -2, the phosphatidylinositol 3-kinase pathway, or Src kinases. Thus nucleotides regulate proliferation of human lung epithelial cells by a novel pathway. The stimulatory effect of UTP, but not ATP, in A549 cells is attenuated by preincubation with interleukin-1beta and interleukin-6, but not tumor necrosis factor-alpha. This indicates an important role for the pyrimidine-activated P2Y receptor in the inflammatory response of lung epithelia. ATP antagonizes the antiproliferative effect of the anticancer drugs paclitaxel and etoposide, whereas it enhances the activity of cisplatin about fourfold. Thus pathways activated by extracellular nucleotides differentially control proliferation of lung epithelial tumor cells.
 ...
PMID:ATP- and UTP-activated P2Y receptors differently regulate proliferation of human lung epithelial tumor cells. 1269 58

Murine bone marrow-derived dendritic cells (DC), stimulated with lipopolysaccharide (LPS) and/or LPS+interferon-gamma (IFN-gamma), secrete a variety of inflammatory mediators which may modulate their functions. We have examined the potential for exogenous prostanoids, acting in a paracrine fashion, and endogenous prostanoids, acting in an autocrine fashion, to regulate secretion of tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), IL-10, and IL-12 in DC. In order to identify receptors mediating these effects, DC were treated in vitro with receptor-selective prostanoids. Agonists of cyclic AMP-elevating receptors, namely, prostaglandin E(2) (PGE(2)), butaprost (EP(2) receptor), iloprost (IP receptor), and BW245C (DP receptor), dose-dependently inhibited the release of IL-6, TNF-alpha, and IL-12 and enhanced the release of IL-10 from LPS-stimulated DC, with TNF-alpha secretion being the most strongly affected. In contrast, 15-deoxy-Delta(12,14)-PGJ(2)-an activator of nuclear peroxisome proliferator-activated receptor-gamma (PPAR-gamma) receptors-inhibited release of all tested cytokines. Exogenous prostanoids, cyclic AMP-elevating analogs, lost their ability to modulate cytokine release in cells pre-incubated for 4 h with LPS, indicating that prostanoids may affect DC functions during initial phases of LPS stimulation only. Sulprostone and (+)-fluprostenol failed to modulate any of responses tested, suggesting lack of involvement/expression of EP(1), EP(3), and FP receptors in DC activation. In order to examine the role of endogenous prostanoids, DC were treated with inhibitors of cyclooxygenases (COX). At concentrations that completely blocked PGE(2) release, neither indomethacin (nonselective inhibitor) nor rofecoxib (COX-2-selective inhibitor) influenced cytokine release from LPS-stimulated DC. Thus, cytokine release from LPS-stimulated DC does not seem to be autoregulated by endogenous prostanoids, whereas in vivo regulatory function may be fulfilled in a paracrine manner by PGD(2), PGE(2), and PGI(2) released from neighboring cells.
 ...
PMID:Exogenous but not endogenous prostanoids regulate cytokine secretion from murine bone marrow dendritic cells: EP2, DP, and IP but not EP1, EP3, and FP prostanoid receptors are involved. 1278 3

In recent studies, sodium arsenite (SA) inhibited IL-6 production in cultured intestinal epithelial cells, at least in part by downregulating the activity of nuclear factor-kappaB (NF-kappaB). The influence of SA on the activity of other transcription factors regulating the interleukin-6 (IL-6) gene in enterocytes is not known. We tested the effect of SA on the activity of CCAAT/enhancer binding protein (C/EBP), activating protein-1 (AP-1), and CRE binding proteins in IL-1beta-treated Caco-2 cells. DNA binding activity was determined by electrophoretic mobility shift assay (EMSA) and transcriptional activity by transfecting cells with luciferase reporter plasmids containing promoter constructs with binding sites for the individual transcription factors. DNA binding activity for all three transcription factors was increased after treatment with SA or IL-1beta. In contrast, SA inhibited transcriptional activity of AP-1 and CRE binding proteins but not C/EBP. Additional experiments provided evidence that the inhibition of AP-1 and CRE mediated transcriptional activity was associated with, and probably caused by, increased expression of the transcriptional repressor cyclic AMP response element modulator (CREM)alpha. The present results are consistent with the concept that SA inhibits IL-6 production in stimulated enterocytes by downregulating the transcriptional activity of several, but not all, IL-6-related transcription factors. Because of the multiple important biological functions of IL-6 in the enterocyte and gut mucosa, methods to regulate enterocyte IL-6 production have significant clinical implications.
 ...
PMID:Sodium arsenite downregulates transcriptional activity of AP-1 and CRE binding proteins in IL-1beta-treated Caco-2 cells by increasing the expression of the transcriptional repressor CREMalpha. 1452 96


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>